ABSTRACT Colorectal cancer (CRC) represents the fourth most commonly diagnosed cancer with 134,490 new cases each year. Unfortunately, CRC results in a disproportionate number of deaths (49,190 projected in 2016) due to advanced stage at diagnosis, the aggressive phenotype of the disease and lack of effective therapeutics. Greater than 90% of CRC patients possess activating mutations in the WNT signaling pathway. WNT pathway activation is a critical step in the initiation of CRC tumorigenesis. Currently, there are no FDA-approved drugs or drugs in late-stage clinical trials that target the WNT pathway. As a result, there is an urgent need for the development of inhibitors of the WNT pathway to treat not only CRC, but other WNT-driven cancers. StemSynergy Therapeutics Inc. (SSTI) is a biopharmaceutical company focused on the discovery, development and commercialization of novel therapeutic approaches to target critical cancer stem cells, including WNT, Hedgehog and Notch. SSTI has identified a class of small molecules that regulate WNT signaling via activation of Casein Kinase 1?? In this application, we describe detailed characterization of mechanism of action, demonstrate SST-215 functions downstream of activating mutations found in CRC to produce excellent in vitro potency in a range of CRC cell lines and provide significant in vivo efficacy data using various genetic and xenograft models in mice. Significantly, SST-215 does NOT affect normal GI architecture, which is in contrast to two other major classes of WNT inhibitors currently being developed where GI toxicity is dose limiting. This Phase I application outlines the development of SST- 215 as an orally bioavailable drug for dosing in humans that would complement or supersede the formulation that we are progressing through preclinical development and into clinical trials for metastatic CRC. The WNT pathway plays a role in many different cancer subtypes and because there are no drugs on the market that target the WNT pathway, by continuing to move SST-215 through the oncology development pipeline, SSTI has the potential to improve and prolong the lives of millions of cancer patients worldwide. The multi-disciplinary R&D team at SSTI has strong credentials and experience in all relevant areas, enabling us to complete the key science and business aspects of the development.